DESCRIPTION: (from applicant's abstract) The long term goal of this project is to understand the molecular mechanisms by which presynaptic proteins mediate neurotransmitter release, with a view towards providing a framework for our eventual understanding of how these fundamental neural mechanisms might become altered in pathological conditions, such as mental health disorders. The objective of this project is to determine the function of mSec6 and mSec8, two newly cloned components of a novel mult-protein complex in the nerve terminals. It has been proposed that the mammalian brain sec6/8 complex may be a key player in establishing exocytic sites on neuronal membranes during development and in synaptic vesicle docking and fusion in mature nerve terminals. In this application, we will test this hypothesis by directly examining the in vivo role of mSec6 and mSec8 using specific gene targeting technology. Conditional mutant mice lacking either or both mSec6 and mSec8 will be generated using the Cre/LoxP system, and the effects of these mutations on neuronal development and synaptic transmission will be characterized using a battery of ultrastructural, biochemical, cell biological, and electrophysiological analyses. Experiments will focus on the following specific areas: (A) to explore the potential role of these proteins in determining the polarity of neurites and the formation of synapses; (B) to investigate the possible role of these proteins in docking of the synaptic vesicles; (C) to investigate the possible role of these proteins in neurotransmitter release and synaptic plasticity. These studies will not only yield novel insight into the molecular mechanisms underlying neurotransmitter release and synaptic plasticity, but will also provide fundamental information towards our eventual understanding of the neural processes that go awry in complex mental health disorders.